title: Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells.
abstract: Hepatic injury induced by ischemia and reperfusion is an important clinical problem after liver resection or transplantation. Neutrophils are known to mediate the organ injury, but the precise mechanisms leading to hepatic neutrophil recruitment are undefined. Two CXC chemokines, macrophage inflammatory protein-2 (MIP-2) and KC, are potently chemotactic for neutrophils in vitro and have been reported to be involved in neutrophil-dependent inflammatory tissue injury. The objective of the present study was to determine the roles of MIP-2 and KC in the induction of hepatic ischemia/reperfusion injury. C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia followed by reperfusion. Hepatic injury was associated with neutrophil sequestration, edema, and elevated serum levels of hepatic transaminases. The expression of MIP-2 messenger RNA (mRNA) was induced within 3 hours after reperfusion, before any detectable increase in neutrophil accumulation, and was also increased to a greater extent in the ischemic lobe after 9 hours of reperfusion. These data suggest that MIP-2 may be involved in the initial recruitment of neutrophils to the ischemic lobe. In contrast, KC mRNA expression was not increased after 3 hours of reperfusion but after 9 hours increased equivalently in both ischemic and nonischemic lobes, suggesting a more generalized role in neutrophil recruitment. Neutralization of MIP-2 or KC resulted in significant decreases in hepatic neutrophil accumulation, edema, and hepatocellular injury. These data suggest that the local expression of MIP-2 and KC are important mediators involved in neutrophil-dependent hepatic injury induced by ischemia and reperfusion in mice.
authors.affiliation: Center for Applied Microcirculatory Research, University of Louisville, KY 40292, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Lentsch
authors.forename: H
authors.initials: H
authors.lastname: Yoshidome
authors.forename: W G
authors.initials: WG
authors.lastname: Cheadle
authors.forename: F N
authors.initials: FN
authors.lastname: Miller
authors.forename: M J
authors.initials: MJ
authors.lastname: Edwards
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D007116:Immunization, Passive; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D015846:Monokines / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D013997:Time Factors
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D015846:Monokines; D012333:RNA, Messenger; C074302:keratinocyte-derived chemokines; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase